The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (Maroteaux and Lamy, 1968; Langer et al., 1969). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. Classification of Achondrogenesis Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). Borochowitz et al. (1988) suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA, corresponding to the cases originally published by Houston et al. (1972) and Harris et al. (1972), and type IB (600972), corresponding to the case originally published by Fraccaro (1952). Analysis of the case reported by Parenti (1936) by Borochowitz et al. (1988) suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (200610). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. Genetic Heterogeneity of Achondrogenesis Achondrogenesis type IB (ACG1B; 600972) is caused by mutation in the DTDST gene (606718), and achondrogenesis type II (ACG2; 200610) is caused by mutation in the COL2A1 gene (120140).

COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone but are most common in the extremities. DI is characterized by gray or brown teeth that may appear translucent, wear down, and break easily. COL1A1/2-OI has been classified into four types based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four more common OI types are now referred to as follows: Classic non-deforming OI with blue sclerae (previously OI type I). Perinatally lethal OI (previously OI type II). Progressively deforming OI (previously OI type III). Common variable OI with normal sclerae (previously OI type IV).

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized clinically by bone fragility and increased susceptibility to fractures. Osteogenesis imperfecta type IX (OI9) is a severe autosomal recessive form of the disorder (summary by van Dijk et al., 2009).

Osteogenesis imperfecta is a connective tissue disorder characterized by bone fragility and low bone mass. OI type VII is an autosomal recessive form of severe or lethal OI (summary by Barnes et al., 2006).

Autosomal recessive osteopetrosis-7 (OPTB7) is an osteoclast-poor form of osteopetrosis with hypogammaglobulinemia. Clinical features include visual impairment, recurrent respiratory infections, poor growth, developmental delay, and increased bone density (Guerrini et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive osteopetrosis, see OPTB1 (259700).

Greenberg dysplasia (GRBGD), also known as hydrops-ectopic calcification-moth-eaten (HEM) skeletal dysplasia, is a rare autosomal recessive osteochondrodysplasia characterized by gross fetal hydrops, severe shortening of all long bones with a moth-eaten radiographic appearance, platyspondyly, disorganization of chondroosseous calcification, and ectopic ossification centers. It is lethal in utero. Patient fibroblasts show increased levels of cholesta-8,14-dien-3-beta-ol, suggesting a defect of sterol metabolism (summary by Konstantinidou et al., 2008). Herman (2003) reviewed the cholesterol biosynthetic pathway and 6 disorders involving enzyme defects in postsqualene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome (SLOS; 270400), desmosterolosis (602398), X-linked dominant chondrodysplasia punctata (CDPX2; 302960), CHILD syndrome (308050), lathosterolosis (607330), and HEM skeletal dysplasia.

Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type X is an autosomal recessive form characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclera (Christiansen et al., 2010).

Osteogenesis imperfecta type XVI (OI16) is characterized by prenatal onset of multiple fractures of ribs and long bones, blue sclerae, decreased ossification of the skull, and severe demineralization. Heterozygous family members may exhibit recurrent fractures with minimal trauma, osteopenia, and blue sclerae (Keller et al., 2018; Lindahl et al., 2018).

Complex lethal osteochondrodysplasia of the Symoens-Barnes-Gistelinck type is characterized by severe skeletal osteopenia, microcephaly, multiple fractures, and congenital anomalies including ascites, pleural effusion, and intracranial ventriculomegaly (Symoens et al., 2015).